Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis
Feng Peng, Guy R. Humphrey, Kevin M. Maloney, Dan Lehnherr, Mark Weisel, François Lévesque, John R. Naber, Andrew P. J. Brunskill, Patrick Larpent, Si‐Wei Zhang, Alfred Y. Lee, Rebecca A. Arvary, Claire H. Lee, Daniel Bishara, Karthik Narsimhan, E. B. Sirota, Michael Whittington
Abstract
Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are described, which provide better alternatives to the initial four-step supply route. These new routes include a coumarin fragmentation approach in flow, a rhenium-catalyzed isopropylation of mequinol, and a bromination/methoxylation of 2-isopropylphenol. After exploring several approaches, a robust two-step process for the preparation of 3 from the commodity starting material 2-isopropylphenol was developed. The optimized route employs a highly regioselective bromination. After isolating the bromophenol DABCO cocrystal, a copper-catalyzed methoxylation delivers 3 in high yield. This route is successfully demonstrated at the plant scale with low process mass intensity and cost.